1. Field of the Invention
The invention relates to compounds that advantageously inhibit the enzymatic activity of picornaviral 3C proteases, especially rhinovirus 3C proteases (RVPs), and that retard viral growth in cell culture. The invention also relates to the use of such compounds in pharmaceutical compositions and therapeutic treatments for rhinoviral infections. The invention further relates to processes for synthesizing such compounds and intermediate compounds useful in such syntheses.
2. Related Background Art
The picornaviruses are a family of tiny non-enveloped positive-stranded RNA-containing viruses that infect humans and other animals. These viruses include the human rhinoviruses, human polioviruses, human coxsackieviruses, human echoviruses, human and bovine enteroviruses, encephalomyocarditis viruses, meningitis virus, foot and mouth viruses, hepatitis A virus, and others. The human rhinoviruses are a major cause of the common cold. To date, there are no effective therapies that cure the common cold, only treatments that relieve the symptoms.
Picornaviral infections may be treated by inhibiting the proteolytic 3C enzymes. These enzymes are required for the natural maturation of the picornaviruses. They are responsible for the autocatalytic cleavage of the genomic, large polyprotein into the essential viral proteins. Members of the 3C protease family are cysteine proteases, where the sulfhydryl group most often cleaves the glutamine-glycine amide bond. Inhibition of 3C proteases is believed to block proteolytic cleavage of the polyprotein, which in turn can retard the maturation and replication of the viruses by interfering with viral particle production. Therefore, inhibiting the processing of this cysteine protease with selective molecules that are specifically recognized should represent an important and useful approach to treat and cure viral infections of this nature and, in particular, the common cold.
Some inhibitors of the enzymatic activity of picornaviral 3C proteases (i.e., antipicornaviral compounds) have been recently discovered. See, for example: U.S. Pat. Nos. 5,856,530; 5,962,487; U.S. patent application Ser. No. 08/991,282, filed Dec. 16, 1997, by Dragovich et al.; and U.S. patent application Ser. No. 09/301,977, filed Apr. 29, 1999, by Dragovich et al. See also: Dragovich et al., xe2x80x9cStructure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors . . . , xe2x80x9d J. Med. Chem. (1999), Vol. 42, No. 7, 1203-1212, 1213-1224; and Dragovich et al., xe2x80x9cSolid-phase Synthesis of Irreversible Human Rhinovirus 3C Protease Inhibitors . . . ,xe2x80x9d Bioorg. and Med. Chem. (1999), Vol. 7, 589-598. There is still a desire, however, to discover compounds that are especially potent antipicornaviral agents.
The present invention relates to compounds of the general formula I: 
wherein:
Ra may be selected from an aryl, heteroaryl, alkyl, alkenyl, amino, cycloalkyl or heterocycloalkyl group, provided that Ra is not pyrrolidinyl, where the aryl, heteroaryl, alkyl, alkenyl, amino, cycloalkyl or heterocycloalkyl group is unsubstituted or substituted with one or more suitable substituents;
Rc is a substituent having the formula: 
wherein:
Rf and Rg are each independently H or lower alkyl;
m is 0 or 1;
p is an integer of from 0 to 5;
A1 is CH or N;
when p is 1, 2, 3, 4, or 5, A2 is C(Rh)(Ri), N(Rj), S, S(O), S(O)2, or O, and when p is 0, A2 is C(Rh)(Ri)(Rj), N(Ri)(Rj), S(Ri), S(O)(Ri), S(O)2(Ri), or O(Ri), where each Rh, Ri and Rj is independently H or a lower alkyl group;
each A3 present is independently C(Rh)(Ri), N(Rj), S, S(O), S(O)2, or O; where each Rh, Ri and Rj is independently H or lower alkyl;
when p is 1, 2, 3, 4, or 5, A4 is N(Rk), C(Rh)(Ri), or O; and when p is 0 (i.e., A3 is not present), A4 is N(Rk)(Rl), C(Rh)(Ri)(Rj), and O(Rl), where each Rh, Ri and Rj is independently H or lower alkyl, each Rk is H, alkyl, aryl, or acyl, and each Rl is H, alkyl, or aryl;
provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A1, (A2)m, (A3)p, A4, and Cxe2x95x90O, where each dotted line in the ring depicts a single bond when A2 is present (i.e., m=1) and a hydrogen atom when A2 is absent (i.e., m=0);
Rd is H, halogen, hydroxyl or an alkyl, alkoxy or alkylthio group, where the alkyl, alkoxy or alkylthio group is unsubstituted or substituted with one or more suitable substituents;
Rb is H or an alkyl group, unsubstituted or substituted with one or more suitable substituents;
Z and Z1 are each independently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, xe2x80x94C(O)Rn xe2x80x94CO2Rnxe2x80x94CN, xe2x80x94C(O)NRnRo, xe2x80x94C(O)NRnORo, xe2x80x94C(S)Rn, xe2x80x94C(S)ORnxe2x80x94C(S)NRnRo, xe2x80x94C(xe2x95x90NRn)Ro, xe2x80x94C(xe2x95x90NRn)ORo, xe2x80x94NO2, xe2x80x94SORo, xe2x80x94SO2Rn, xe2x80x94SO2NRnRo, xe2x80x94SO2(NRn)(ORo), xe2x80x94SONRn, xe2x80x94SO3Rn, xe2x80x94PO(ORn)2, xe2x80x94PO(ORn)(ORo), xe2x80x94PO(NRnRo)(ORp), xe2x80x94PO(NRnRo)(NRpRq), xe2x80x94C(O)NRnNRoRp, xe2x80x94C(S)NRnNRoRp, where Rn, Ro, Rp and Rq are each independently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted or substituted with one or more suitable substituents, or where any two of the Rn, Ro, Rp and Rq, taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which may be optionally substituted,
or Z and Rd, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Rd are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group,
or Z and Z1, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above (except for moieties that cannot form the cycloalkyl or heterocycloalkyl group); and
In another embodiment of the compounds of the above Formula I,
A1 is CH or N; A2 is C(Rh)(Ri), N(Rj), S, S(O), S(O)2, or O; where each Rh, Ri and Rj is independently H or lower alkyl; each A3 present is independently C(Rh)(Ri), N(Rj), S, S(O), S(O)2, or O; where each Rh, Ri and Rj is independently H or lower alkyl; when p is 1, 2, 3, 4, or 5, A4 is N(Rk), C(Rh)(Ri), or O; and when p is 0 (i.e., A3 is not present), A4 is N(Rk)(Rl), C(Rh)(Ri)(Rj), and O(Rl), where each Rh, Ri and Rj is independently H or lower alkyl, each Rk is H, alkyl, aryl, or acyl, and each Rl is H, alkyl, or aryl; provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A1, (A2)m, (A3)p, A4, and Cxe2x95x90O, where each dotted line in the ring depicts a single bond when A2 is present (i.e., m=1) and a hydrogen atom when A2 is absent (i.e., m=0); and Z and Z1 are each independently H, F, a unsubstituted or substituted alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group, xe2x80x94C(O)Rn, xe2x80x94CO2Rn, xe2x80x94CN, xe2x80x94C(O)NRnRo, xe2x80x94C(O)NRnORo, xe2x80x94C(S)Rn, xe2x80x94C(S)NRnRo, xe2x80x94NO2, xe2x80x94SORo, xe2x80x94SO2Rn, xe2x80x94SO2NRnRo, xe2x80x94SO2(NRn)(ORo), xe2x80x94SONRn, xe2x80x94SO3Rn, xe2x80x94PO(ORn)2, xe2x80x94PO(ORn)(ORo), xe2x80x94PO(NRnRo)(ORp), xe2x80x94PO(NRnRo)(NRpRq), xe2x80x94C(O)NRnNRoRp, xe2x80x94C(S)NRnNRoRp, where each Rn, Ro, Rp and Rq are independently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted or substituted with one or more suitable substituents, or where any two of the Rn, Ro, Rp and Rq, taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which may be optionally substituted, form a heterocycloalkyl group, provided that Z and Z1 are not both H; or Z and Rd, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Rd are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group; or Z and Z1, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group.
One embodiment of this invention relates to compounds useful for inhibiting the activity of picornaviral 3C proteases having the following general formula: 
wherein Ra1 is a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, provided that Ra1 is not a substituted pyrrolidinyl, where the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents; and
Rb, Rc, Rd, Z and Z1 are as defined above.
Another embodiment of this invention relates to compounds useful for inhibiting the activity of picornaviral 3C proteases having the following general formula: 
wherein Ra2 is an alkyl, aryl or heteroaryl group, where the alkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents; and
Rb, Rc, Rd, Z and Z1 are as defined above.
This invention also relates to compounds useful for inhibiting the activity of picornaviral 3C proteases having the following general formula: 
wherein Ra3 is an aryl, heterocycloalkyl, heteroaryl or arylaminocarbonyl group, where the aryl, heterocycloalkyl, heteroaryl or arylaminocarbonyl group is unsubstituted or substituted with one or more suitable substituents;
Re is H, halogen, hydroxyl, or an alkyl, alkoxy or alkylthio group, where the alkyl, alkoxy or alkylthio group is unsubstituted or substituted with one or more suitable substituents; and
Rb, Rc, Rd, Z and Z1 are as defined above.
This invention relates to compounds useful for inhibiting the activity of picornaviral 3C proteases having the general formula: 
wherein Ra4 is an aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxy, heterocycloalkyloxy, aryl, cycloalkyl, or heteroaryl group, where the aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxy, heterocycloalkyloxy, aryl, cycloalkyl, or heteroaryl group is unsubstituted or substituted with one or more suitable substituents; and
Rb, Rc, Rd, Re, Z and Z1 are as defined above.
In addition to compounds of the Formulae I-V, antipicornaviral agents of the invention include prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts and solvates of such compounds.
In accordance with a convention used in the art, 
is used in structural formulas herein to depict the bond that is the point of attachment of the substituent to the backbone structure. Where chiral carbons are included in chemical structures, unless a particular orientation is depicted, both stereoisomeric forms are intended to be encompassed.
As used herein, the term xe2x80x9calkylxe2x80x9d represents a straight- or branched-chain saturated or unsaturated hydrocarbon, containing 1 to 10 carbon atoms, that may be unsubstituted or substituted by one or more of the substituents described below. Exemplary alkyl substituents include, but are not limited to, methyl (Me), ethyl (Et), propyl, isopropyl, butyl, isobutyl, t-butyl, ethenyl, propenyl, butenyl, pentenyl, ethynyl, butynyl, propynyl, pentynyl, hexynyl and the like. The term xe2x80x9clower alkylxe2x80x9d refers to an alkyl group containing from 1 to 4 carbon atoms.
xe2x80x9cCycloalkylxe2x80x9d represents a group comprising a non-aromatic monocyclic, bicyclic, or tricyclic hydrocarbon containing from 3 to 14 carbon atoms that may be unsubstituted or substituted by one or more of the substituents described below and may be saturated or partially unsaturated, mono- or poly-carbocyclic ring, preferably having 5-14 ring carbon atoms. Exemplary cycloalkyls include monocyclic rings having from 3-7, preferably 3-6, carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, that may be fully saturated or partially unsaturated. Illustrative examples of cycloalkyl groups include the following: 
xe2x80x9cHeterocycloalkylxe2x80x9d represents a group comprising a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical, which may be unsubstituted or substituted by one or more of the substituents described below and may be saturated or partially unsaturated, containing 3 to 18 ring atoms and which includes 1 to 5 hetero atoms selected from nitrogen, oxygen and sulfur, and to which may be fused one or more cycloalkyl groups, aryl groups, or heteroaryl groups. Illustrative examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, chromenyl, tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl, 1,5,9-triazacyclododecyl, and the like. Illustrative examples of heterocycloalkyl groups include the following moieties: 
wherein R is alkyl, aryl, cycloalkyl, heterocycloalkyl, hydroxyl or represents a formula of a compound of this invention.
xe2x80x9cArylxe2x80x9d represents a group comprising an aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing from 6 to 18 carbon ring atoms, which may be unsubstituted or substituted by one or more of the substituents described below. Illustrative examples of aryl groups include the following moieties: 
xe2x80x9cHeteroarylxe2x80x9d represents a group comprising an aromatic monovalent monocyclic, bicyclic, or tricyclic radical, containing 5 to 18 ring atoms, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents described below. As used herein, the term xe2x80x9cheteroarylxe2x80x9d is also intended to encompass the N-oxide derivative (or N-oxide derivatives, if the heteroaryl group contains more than one nitrogen such that more than one N-oxide derivative may be formed) of the nitrogen-containing heteroaryl groups described herein. Illustrative examples of heteroaryl groups include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzo[b]thienyl, naphtho[2,3-b]thianthrenyl, isobenzofuranyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl, quinzolinyl, benzothiazolyl, benzimidazolyl, benzofuranyl, tetrahydroquinolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, and phenoxazinyl. Illustrative examples of N-oxide derivatives of heteroaryl groups include, but are not limited to, pyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, triazinyl N-oxide, isoquinolyl N-oxide, and quinolyl N-oxide. Further examples of heteroaryl groups include the following moieties: 
wherein R is alkyl, aryl, cycloalkyl, heterocycloalkyl, hydroxyl or represents a formula of a compound of this invention.
As indicated herein, the alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups may be optionally substituted by one or more substituents. The term xe2x80x9coptionally substitutedxe2x80x9d is intended to expressly indicate that the specified group is unsubstituted or substituted by one or more suitable substituents. Various groups may be unsubstituted or substituted (i.e., they are optionally substituted) as indicated. The term xe2x80x9csubstituentxe2x80x9d or xe2x80x9csuitable substituentxe2x80x9d is intended to mean any suitable substituent that may be recognized or selected, such as through routine testing, by those skilled in the art.
The term xe2x80x9csuitable substituentxe2x80x9d represents a substituent that is optionally present on any of the above alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl groups, described herein, and is selected from alkyl (except for alkyl) haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, nitro, amino, hydroxamino, cyano, halo, hydroxyl, alkoxy, alkylenedioxy, aryloxy, cycloalkoxy, heterocycloalkoxy, heteroaryloxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy, aryloxycarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyloxy, cycloalkyoxycarbonyl, heteroarylcarbonyl, heteroarylcarbonyloxy, heteroaryloxycarbonyl, heterocycloalkylcarbonyl, heterocycloalkylcarbonyloxy, heterocycloalkyoxycarbonyl, carboxyl, carbamoyl, formyl, keto (oxo), thioketo, sulfo, alkylamino, cycloalkylamino, arylamino, heterocycloalkylamino, heteroarylamino, dialkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heterocycloalkylaminocarbonyl, heteroarylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, cycloalkylaminothiocarbonyl, arylaminothiocarbonyl, heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl, arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heterocycloalkylcarbonylamino, heteroarylcarbonylamino, alkylthiocarbonylamino, cycloalkylthiocarbonylamino, arylthiocarbonylamino, heterocycloalkylthiocarbonylamino, heteroarylthiocarbonylamino, alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino, arylsulfonylamino, mercapto, alkylthio, arylthio, and heteroarylthio groups, where any of the alkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, heteroaryl moieties present in the above substituents may be further substituted with one or more substituents selected from nitro, amino, cyano, halo, haloalkyl, haloaryl, hydroxyl, keto, hydroxamino, alkylamino, dialkylamino, mercapto, and unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, aryloxy, alkylthio or arylthio groups and where any of the aryl or heteroaryl moieties may be substituted with alkylenedioxy. Preferred xe2x80x9csuitable substituentsxe2x80x9d include halo, nitro, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, xe2x80x94C(O)Rr, xe2x80x94C(O)ORr, xe2x80x94OC(O)Rr, xe2x80x94ORr, xe2x80x94SRr, xe2x80x94C(O)NRsRt, and xe2x80x94NRsRt, where each Rr, Rs, and Rt are independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and each alkyl, aryl, or heteroaryl substituent may optionally be further substituted with one or two substituents selected from unsubstituted lower alkyl, unsubstituted lower alkoxy, nitro, halo, hydroxy or phenyl, where the phenyl group is unsubstituted or substituted with one or more substituents independently selected from alkyl, haloalkyl, alkylenedioxy, nitro, amino, hydroxamino, alkylamino, dialkylamino, halo, hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto, alkylthio or arylthio groups.
If the substituents themselves are not compatible with the synthetic methods of this invention, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions used in these methods. The protecting group may be removed at a suitable point in the reaction sequence of the method to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley and Sons, NY (1999), which is incorporated herein by reference in its entirety. In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used in the methods of this invention. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful in an intermediate compound in the methods of this invention or is a desired substituent in a target compound.
The terms xe2x80x9chalogenxe2x80x9d and xe2x80x9chaloxe2x80x9d represent chloro, fluoro, bromo or iodo substituents. xe2x80x9cHeterocyclexe2x80x9d is intended to mean a heteroaryl or heterocycloalkyl group. xe2x80x9cAcylxe2x80x9d is intended to mean a xe2x80x94C(O)xe2x80x94R radical, where R is an alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group. xe2x80x9cAcyloxyxe2x80x9d is intended to mean an xe2x80x94OC(O)xe2x80x94R radical, where R is an alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group. xe2x80x9cThioacylxe2x80x9d is intended to mean a xe2x80x94C(S)xe2x80x94R radical, where R is an alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group. xe2x80x9cSulfonylxe2x80x9d is intended to mean an xe2x80x94SO2xe2x80x94 biradical. xe2x80x9cSulfenylxe2x80x9d is intended to mean an xe2x80x94SOxe2x80x94 biradical. xe2x80x9cSulfoxe2x80x9d is intended to mean an xe2x80x94SO2H radical. xe2x80x9cSulfoxidexe2x80x9d is intended to mean a xe2x80x94SO3xe2x88x92 radical. xe2x80x9cHydroxyxe2x80x9d is intended to mean the radical xe2x80x94OH. xe2x80x9cAminexe2x80x9d or xe2x80x9cAminoxe2x80x9d is intended to mean the radical xe2x80x94NH2. xe2x80x9cAlkylaminoxe2x80x9d is intended to mean the radical xe2x80x94NHRa, where Ra is an alkyl group. xe2x80x9cDialkylaminoxe2x80x9d is intended to mean the radical xe2x80x94NRaRb, where Ra and Rb are each independently an alkyl group, and is intended to include heterocycloalkyl groups, where Ra and Rb, taken together, form a heterocyclic ring that includes the amine nitrogen. xe2x80x9cHydroxaminoxe2x80x9d is intended to mean the radical xe2x80x94Nxe2x80x94OH. xe2x80x9cAlkoxyxe2x80x9d is intended to mean the radical xe2x80x94ORa, where Ra is an alkyl group. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, and the like. xe2x80x9cLower alkoxyxe2x80x9d groups have alkyl moieties having from 1 to 4 carbons. xe2x80x9cAlkylenedioxyxe2x80x9d is intended to mean the divalent radical xe2x80x94ORaOxe2x80x94 which is bonded to adjacent atoms on an aryl or heteroaryl moiety (e.g., adjacent atoms on a phenyl or naphthyl ring), where Ra is a lower alkyl group. xe2x80x9cAlkoxycarbonylxe2x80x9d is intended to mean the radical xe2x80x94C(O)ORa, where Ra is an alkyl group. xe2x80x9cAlkylsulfonylxe2x80x9d is intended to mean the radical xe2x80x94SO2Ra, where Ra is an alkyl group. xe2x80x9cAlkylaminocarbonylxe2x80x9d is intended to mean the radical xe2x80x94C(O)NHRa, where Ra is an alkyl group. xe2x80x9cDialkylaminocarbonylxe2x80x9d is intended to mean the radical xe2x80x94C(O)NRaRb, where Ra and Rb are each independently an alkyl group. xe2x80x9cMercaptoxe2x80x9d is intended to mean the radical xe2x80x94SH. xe2x80x9cAlkylthioxe2x80x9d is intended to mean the radical xe2x80x94SRa, where Ra is an alkyl group. xe2x80x9cCarboxylxe2x80x9d is intended to mean the radical xe2x80x94C(O)OH. xe2x80x9cKetoxe2x80x9d or xe2x80x9coxoxe2x80x9d is intended to mean the radical xe2x95x90O. xe2x80x9cThioketoxe2x80x9d is intended to mean the radical xe2x95x90S. xe2x80x9cCarbamoylxe2x80x9d is intended to mean the radical xe2x80x94C(O)NH2. xe2x80x9cCycloalkylalkylxe2x80x9d is intended to mean the radical -alkyl-cycloalkyl, where alkyl and cycloalkyl are defined as above, and is exemplified by the bonding arrangement present in the groups xe2x80x94CH2-cyclohexane or xe2x80x94CH2-cyclohexene. xe2x80x9cArylalkylxe2x80x9d is intended to mean the radical -alkylaryl, where alkyl and aryl are defined as above, and is exemplified by the bonding arrangement present in a benzyl group. xe2x80x9cAminocarbonylalkylxe2x80x9d is intended to mean the radical -alkylC(O) NH2 and is exemplified by the bonding arrangement present in the group xe2x80x94CH2CH2C(O)NH2. xe2x80x9cAlkylaminocarbonylalkylxe2x80x9d is intended to mean the radical -alkylC(O)NHRa, where Ra is an alkyl group and is exemplified by the bonding arrangement present in the group xe2x80x94CH2CH2C(O)NHCH3. xe2x80x9cAlkylcarbonylaminoalkylxe2x80x9d is intended to mean the radical -alkylNHC(O)-alkyl and is exemplified by the bonding arrangement present in the group xe2x80x94CH2NHC(O)CH3. xe2x80x9cDialkylaminocarbonylalkylxe2x80x9d is intended to mean the radical -alkylC(O)NRaRb, where Ra and Rb are each independently an alkyl group. xe2x80x9cAryloxyxe2x80x9d is intended to mean the radical xe2x80x94ORc, where Rc is an aryl group. xe2x80x9cHeteroaryloxyxe2x80x9d is intended to mean the radical xe2x80x94ORd, where Rd is a heteroaryl group. xe2x80x9cArylthioxe2x80x9d is intended to mean the radical xe2x80x94SRc, where Rc is an aryl group. xe2x80x9cHeteroarylthioxe2x80x9d is intended to mean the radical xe2x80x94SRd, where Rd is a heteroaryl group. The alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups and the substituents containing these groups, as defined hereinabove, may be optionally substituted by at least one other substituent. The term xe2x80x9coptionally substitutedxe2x80x9d is intended to expressly indicate that the specified group is unsubstituted or substituted by one or more suitable substituents. Various groups may be unsubstituted or substituted (i.e., they are optionally substituted) as indicated.
If an inventive compound is a base, a desired salt may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
If an inventive compound is an acid, a desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary); an alkali metal or alkaline earth metal hydroxide; or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary, and tertiary amines; and cyclic amines, such as piperidine, morpholine, and piperazine; as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
All compounds of this invention contain at least one chiral center and may exist as single stereoisomers (e.g., single enantiomers or diastereomers), any mixture of stereosisomers (e.g., any mixture of enantiomers or diastereomers) or racemic mixtures thereof. All such single stereoisomers, mixtures and racemates are intended to be encompassed within the broad scope of the present invention. Where the stereochemistry of the chiral carbons present in the chemical structures illustrated herein is not specified, the chemical structure is intended to encompass compounds containing either stereoisomer of each chiral carbon. When used describe a particular compound, the term xe2x80x9coptically purexe2x80x9d is used herein to indicate that the compound is substantially enantiomerically or diastereomerically pure. Compounds that are substantially enantiomerically pure contain at least 90% of a single isomer and preferably contain at least 95% of a single isomer. Compounds that are substantially diastereomerically pure contain at least 90% of a single isomer of each chiral carbon center present in the diastereomer, and preferably contain at least 95% of a single isomer of each chiral carbon. More preferably, when an optically active compound is desired, it contains at least 97.5% of a single isomer and, most preferably, at least 99% of the single isomer. Compounds identified herein as single stereoisomers are meant to describe compounds that are present in a form that contains at least 90% of a single isomer. The terms xe2x80x9cracematexe2x80x9d and xe2x80x9cracemate mixturexe2x80x9d refer to a mixture of equal amounts of enantiomeric compounds, which encompass mixtures of enantiomers and mixtures of enantiomeric diastereomers.
The compounds of this invention may be obtained in stereochemically (e.g., enantiomerically or diastereomerically) pure or substantially stereochemically pure form. Such compounds may be obtained synthetically, according to the procedures described herein using optically pure or substantially optically pure materials. Alternatively, these compounds may be obtained by resolution/separation of a mixture of stereoisomers, including racemic mixtures, using conventional procedures. Exemplary methods that may be useful for the resolution/separation of stereoisomeric mixtures include chromatography and crystallization/re-crystallization. Other useful methods may be found in xe2x80x9cEnantiomers, Racemates, and Resolutions,xe2x80x9d J. Jacques et al., 1981, John Wiley and Sons, New York, N.Y., the disclosure of which is incorporated herein by reference. Preferred stereoisomers of the compounds of this invention are described herein.
The compounds of this invention may also exhibit the phenomenon of tautomerism. The structural formulae herein may depicted one of the possible tautomeric forms but it should be understood that the invention nonetheless encompasses all tautomeric forms of the compound.
The invention also relates to prodrugs, pharmaceutically acceptable salts, pharmaceutically active metabolites, and pharmaceutically acceptable solvates of compounds of the Formula I, II, III, IV and V.
In the compounds of each of the above-described Formulas I to V, Rc is defined to provide structures where m is 1 and p is 1-5 (i.e., both A2 and A3 are present), m is 0 and p is 0 (i.e., both A2 and A3 are absent), m is 0 and p is 1-5 (i.e., A2 is absent and A3 is present) and m is 1 and p is 0 (i.e., A2 is present and A3 is absent). Accordingly, one of ordinary skill in the are will recognize that when both A2 and A3 are present (m is 1 and p is 1-5), the dotted line between A1 and A2 represents a bond and the dotted line between A2 and A3 represents a bond and when both A2 and A3 are absent (m is 0 and p is 0); A2, A3 and the dotted line between these substituents are not present), the remaining dotted line in the structure between A1 and A2 represents a hydrogen (e.g., A1 is CH2 or NH). In embodiments of this invention when A2 is absent and A3 is present (m is 0 and p is 1-5), the dotted line between A1 and A2 represents a hydrogen and the dotted line between A2 and A3 represents a hydrogen (e.g., A1 is CH2 or NH and A3 is CH(Rh)(Ri), NH(Rj), SH, S(O)H, S(O)2H, or OH); and when A2 is present and A3 is absent (m is 1 and p is 0), the dotted line between A1 and A2 represents a bond and A2 is C(Rh)(Ri)(Rj), N(Ri)(Rj), S(Ri), S(O)(Ri), S(O)2(Ri), or O(Ri) or the dotted line between A2 and A3 represents a hydrogen and A2 is CH(Rh)(Ri), NH(Rj), SH, S(O)H, S(O)2H, or OH. In preferred embodiments of the compounds of each of the above-described Formulas, m is 1 and p is 1 or 2 or m is 0 and p is 0 or m is 1 and p is 0. More preferably, when m is 1 and p is 1 or 2, A2 and A3 are both C(Rh)(Ri). More preferably, m is 1 and p is 1.
In especially preferred embodiments of formulas I to V, Rc is selected from xe2x80x94CH2CH2C(O)NH2; xe2x80x94CH2CH2C(O)NH-alkyl; xe2x80x94CH2NHC(O)CH3; and 
where n is 1 or 2. More preferably, Rc is xe2x80x94CH2CH2C(O)NH2 or 
Especially preferred embodiments of this invention are those compounds where Rc is 
In the compounds of formulas I to V, Rd and each Rb are preferably H. In the compounds of formulas IV and V, Re is preferably H or (C1-C6) alkyl.
In each of the formulas I to V, Z and Z1 are each independently H, alkyl, where the alkyl is unsubstituted or substituted with one or more suitable substituents, xe2x80x94CO2n, where Rn is as defined above, or Z and Z1, taken together with the atom to which they are attached, form a heterocycloalkyl group, as defined above, which may be optionally substituted. In one useful embodiment of the compounds of this invention, Z and/or Z1 may be xe2x80x94C(S)ORn, where Rn is as defined above. Such compounds may be prepared using procedures described in K. Hartke, et al., Leibigs Ann. Chem., 321-330 (1989) and K. Hartke, et al., Synthesis, 960-961 (1985). More preferably, the heterocycloalkyl group may optionally contain O, N, S and/or P and may be substituted by one or more of oxo (keto) or thioketo. In another preferred embodiment of this invention, Z and Z1 are each independently selected from H, lower alkyl which is unsubstituted or substituted with one or more suitable substituents, xe2x80x94CO2H, xe2x80x94CO2-alkyl and xe2x80x94CO2-cycloalkyl, or taken together with the atom to which they are attached form a heterocycloalkyl group, which is optionally substituted with one or more of keto or thioketo. In other preferred embodiments of this invention, Z and Z1 are not both H. Most preferably, Z1 is H or lower alkyl and Z is a xe2x80x94CO2H, xe2x80x94CO2-alkyl, xe2x80x94CO2-alkylaryl, xe2x80x94CO2-alkylheteroaryl, xe2x80x94CO2-cycloalkyl group, where the lower alkyl, -alkyl, -cycloalkyl, -alkylaryl and -alkylheteroaryl moieties thereof are unsubstituted or substituted with one or more suitable substituents, or Z1 and Z taken together with the atom to which they are attached form a heterocycloalkyl group, which may be optionally substituted. Exemplary Z groups include, but are not limited to: substituted and unsubstituted xe2x80x94CO2-alkyl groups, which include straight- and branched-chain alkyl groups such as ethoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl and (2,2-dimethylpropyl)-oxycarbonyl, where the ethoxy, t-butoxy, isopropoxy, and (2,2-dimethylpropyl)-oxy moieties thereof are unsubstituted or substituted with one or more suitable substituents; and include substituted and unsubstituted straight and branched-chain arylalkyl and heteroarylalkyl groups, such as benzyloxycarbonyl and pyridylmethyleneoxycarbonyl, where the benzyl and pyridylmethylene moieties thereof are unsubstituted or substituted with one or more suitable substituents; and include substituted and unsubstituted xe2x80x94CO2-cycloalkyl groups such as cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and cycloheptyloxycarbonyl groups, where the cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl moieties thereof are unsubstituted or substituted with one or more suitable substituents, or Z1 and Z taken together with the atom to which they are attached form 
in Formulas I to V.
In another embodiment of this invention, Z1 is H and Z is xe2x80x94CO2CH2CH3, xe2x80x94CO2(CH(CH3)2), xe2x80x94CO2(C(CH3)3), xe2x80x94CO2CH2(C(CH3)3), xe2x80x94CO2(cyclo-C5H9) or Z1 and Z taken together with the atom to which they are attached form 
In yet another embodiment of this invention, Z1 is H and Z is xe2x80x94CO2CH2CH3.
Specific embodiments of this invention comprise compounds having formula II, wherein Ra1 is a (C3-C8)cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, wherein the (C3-C8)cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more substituents independently selected from (C1-C4)alkyl, aryl(C1-C4)alkyl, aryl, (C3-C8)cycloalkyl, heterocycloalkyl, heteroaryl, halo, hydroxyl, nitro, amino, (C1-C4)alkylamino, di-(C1-C4)alkylamino, aryl(C1-C4)alkoxy, aryloxy(C1-C4)alkyl, alkylenedioxy (as a substituent for aryl or heteroaryl), aryloxy, (C3-C8)cycloalkoxy, heteroaryloxy, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, hydroxamino, (C1-C4)alkoxycarbonyl, (C1-C4)alkylcarbonylamino, (C1-C4)alkylcarbonyl, mercapto, alkylthio or arylthio, where the (C1-C4)alkyl and (C3-C8)cycloalkyl moieties thereof are optionally substituted by one or more of (C1-C4)alkyl (except for alkyl), halo, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy and the heterocycloalkyl, aryl or heteroaryl moieties thereof are unsubstituted or are optionally substituted by one or more substituents independently selected from alkyl, haloalkyl, alkylenedioxy, nitro, amino, hydroxamino, alkylamino, dialkylamino, halo, hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto, alkylthio or arylthio groups; preferably, Ra1 is a pyrazolyl, indolyl, chromenyl, benzofuranyl, benzothienyl, benzimidazolyl, triazolyl, quinolyl, thiazolidinyl, quinoxalinyl, phenyl or naphthyl group, where the pyrazolyl, indolyl, chromenyl, benzofuranyl, benzothienyl, benzimidazolyl, triazolyl, quinolyl, thiazolidinyl, quinoxalinyl, phenyl or naphthyl group is unsubstituted or substituted with one or more substituents independently selected from (C1-C4)alkyl, aryl(C1-C4)alkyl, aryl, halo, hydroxyl, nitro, amino, (C1-C4)alkylamino, di-(C1-C4)alkylamino, (C1-C4)alkoxy, aryl(C1-C4)alkoxy, aryloxy(C1-C4)alkyl, methylenedioxy, aryloxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C1-C4)alkoxycarbonyl, (C1-C4)alkylcarbonylamino, or (C1-C4)alkylcarbonyl, where the (C1-C4)alkyl moieties thereof are optionally substituted by one or more of halo, (C1-C4)alkoxy or (C1-C4)haloalkoxy and the aryl moieties thereof are unsubstituted or are optionally substituted by one or more substituents independently selected from alkyl, haloalkyl, alkylenedioxy, nitro, amino, alkylamino, dialkylamino, halo, hydroxyl, alkoxy, haloalkoxy or aryloxy groups; more preferably, Ra1 is a is a pyrazolyl, indolyl, N-methylindolyl, chromenyl, benzofuranyl, benzothienyl, benzimidazolyl, , N-methylbenzimidazolyl, triazolyl, quinolyl, thiazolidinyl, quinoxalinyl, phenyl or naphthyl group, where the pyrazolyl, indolyl, chromenyl, benzofuranyl, benzothienyl, benzimidazolyl, triazolyl, quinolyl, thiazolidinyl, quinoxalinyl, phenyl or naphthyl group is unsubstituted or substituted with one or more substituents independently selected from methyl, ethyl, benzyl, phenethyl, phenyl, naphthyl, halo, hydroxyl, nitro, amino, methylamino, di-methylamino, methoxy, benzyloxy, methylenedioxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, methoxycarbonyl, methylcarbonylamino, benzoyloxymethylene (phenylcarbonyloxymethyl-)or methylcarbonyl;
Rd and each Rb are independently H or C1-C4 alkyl; preferably Rd and each Rb are H; or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate of said compound.
Other specific embodiments of this invention comprise the compounds having the formula III, wherein Ra2 is a (C1-C4)alkyl, aryl or heteroaryl group, wherein the (C1-C4)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is unsubstituted or substituted with one or more suitable substituents; preferably, Ra2 is a (C1-C4)alkyl, phenyl or naphthyl group, where the (C1-C4)alkyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, and the phenyl or naphthyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, methylenedioxy and phenoxy; in specific embodiments, Ra2 is a naphthyl, phenoxyphenyl, 3,5-dimethoxy-phenyl, 3,5-dimethylphenyl or an ethoxycarbonyl-substituted branched (C1-C6) alkyl moiety (derived from the ethyl ester of valine);
Rd and each Rb are independently H or C1-C4 alkyl; preferably Rd and each Rb are H; or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate of said compound.
Additional specific embodiments of this invention comprise compounds having the formula IV, wherein Ra3 is a aryl, heterocycloalkyl, heteroaryl or arylaminocarbonyl group, wherein the aryl, heterocycloalkyl, heteroaryl or arylaminocarbonyl group is unsubstituted or substituted with one or more substituents independently selected from (C1-C4)alkyl, aryl, halo, hydroxyl, nitro, amino, di-(C1-C4)alkylamino (C1-C4)alkoxy, alkylenedioxy (as a substituent for aryl or heteroaryl), aryloxy, where the (C1-C4)alkyl or aryl moieties thereof are unsubstituted or optionally substituted by one or more of (C1-C4)alkyl (except for alkyl), halo, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, alkylenedioxy groups; in specific embodiments, Ra3 is a phenyl or phenylaminocarbonyl group, where the phenyl group or phenyl moiety of the phenylaminocarbonyl group is unsubstituted or substituted with one or more substituents independently selected from (C1-C4)alkyl, halo, hydroxyl, nitro, (C1-C4)alkoxy and alkylenedioxy; in more specific embodiments, Ra3 is a phenyl or phenylaminocarbonyl group, where the phenyl group or phenyl moiety of the phenylaminocarbonyl group is unsubstituted or substituted with one or more substituents independently selected from methyl, halo, hydroxyl, nitro, methoxy, and alkylenedioxy;
Rd, Re and each Rb are independently H or C1-C4 alkyl; preferably Rd and each Rb are H; or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate of said compound.
Yet another specific embodiment of this invention comprises compounds having the formula V, wherein Ra4 is an aryloxy, heteroaryloxy, (C1-C4)alkoxy, (C3-C8)cycloalkoxy, heterocycloalkyloxy, (C3-C8)cycloalkyl, heteroaryl or (C1-C4)alkoxycarbonyl group, wherein the aryloxy, heteroaryloxy, (C1-C4)alkoxy, (C3-C8)cycloalkoxy, heterocycloalkyloxy, (C3-C8)cycloalkyl, heteroaryl or (C1-C4)alkoxycarbonyl group is unsubstituted or substituted with one or more substituents independently selected from (C1-C4)alkyl, aryl, (C3-C8)cycloalkyl, heterocycloalkyl, heteroaryl, halo, hydroxyl, (C1-C4)alkoxy, alkylenedioxy (as a substituent for aryl or heteroaryl), aryloxy, (C3-C8)cycloalkoxy, heteroaryloxy and (C1-C4)alkoxycarbonyl, where the (C1-C4)alkyl, aryl, (C3-C8)cycloalkyl, heterocycloalkyl, heteroaryl moieties thereof are optionally substituted by one or more of (C1-C4)alkyl (except for alkyl), halo, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, alkylenedioxy, aryl or heteroaryl, where the aryl or heteroaryl is unsubstituted or substituted with one or more substituents independently selected from alkyl, haloalkyl, alkylenedioxy, nitro, amino, hydroxamino, alkylamino, dialkylamino, halo, hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto, alkylthio or arylthio groups; in specific embodiments, Ra4 is a phenoxy, or (C1-C4)alkoxycarbonyl group, wherein the phenyl moiety of the phenoxy group is unsubstituted or substituted with one or more substituents independently selected from halo and (C1-C4)alkoxy;
Rd and Rb are independently H or C1-C4 alkyl; preferably Rd and each Rb are H;
Re is H or C1-C6 alkyl; in specific embodiments Re is H or isobutyl, or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate of said compound.
In each of the above-described embodiments of the subject invention, Rc is selected from xe2x80x94CH2CH2C(O)NH2; xe2x80x94CH2CH2C(O)NH-alkyl; xe2x80x94CH2NHC(O)CH3; and 
where n is 1 or 2; preferably, Rc is xe2x80x94CH2CH2C(O)NH2 or 
where n is 1; more preferably, Rc is xe2x80x94CH2CH2C(O)NH2 or 
even more preferably, Rc is 
and
Z1 is H or C1-C4 alkyl and Z is xe2x80x94CO2-alkyl, xe2x80x94CO2-cycloalkyl, xe2x80x94CO2-alkylaryl or xe2x80x94CO2-alkylheterocycloaryl, or Z1 and Z taken together with the atom to which they are attached form 
xe2x80x83preferably, Z1 is H and Z is xe2x80x94CO2CH2CH3, xe2x80x94CO2(CH(CH3)2), xe2x80x94CO2(C(CH3)3), xe2x80x94CO2CH2(C(CH3)3), xe2x80x94CO2(cyclo-C5H9) or Z1 and Z taken together with the atom to which they are attached form 
xe2x80x83more preferably, Z1 is H and Z is xe2x80x94CO2CH2CH3 or Z1 and Z taken together with the atom to which they are attached form 
xe2x80x83even more preferably, Z1 is H and Z is xe2x80x94CO2CH2CH3.
The compounds have antiviral activity against picornaviruses such as human rhinoviruses, human polioviruses, human coxsackieviruses, human echoviruses, human and bovine enteroviruses, encephalomyocarditis viruses, meningitis virus, foot and mouth viruses, hepatitis A virus, and others. Preferably, such compounds, pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates have antipicornaviral activity, more preferably antirhinoviral activity, corresponding to an EC50 less than or equal to 100 xcexcM in the H1-HeLa cell culture assay, more preferably corresponding to an EC50 less than or equal to 10 xcexcM in the H1-HeLa cell culture assay.
Preferred embodiments of this invention comprise the compounds depicted by the formula: 
where Ra and Rc are as defined above.
Other preferred embodiments of this invention comprise the compounds depicted by the formula: 
where Ra1 and Rc are as defined above.
Other preferred embodiments of this invention comprise the compounds depicted by the formula: 
where Ra2 and Rc are as defined above.
Other preferred embodiments of this invention comprise the compounds depicted by the formula: 
where Ra3 and Rc are as defined above.
In other preferred embodiments of compounds of formula I, Ra is selected from: 
where Ru and Rv are selected from H, F, CH3, and C2H5; and Rw, Rx, and Ry are H or a substituent selected from lower alkyl, lower alkoxy, amino, halo, nitro, and hydroxy.
Yet other preferred embodiments of this invention comprise the compounds depicted by the formula: 
where Ra4 is selected from a monosubstituted alkyl or alkoxy, where the substituent is aryl or alkyl. Particularly preferred is Ra4 is xe2x80x94O-aryl or -aryl, where aryl is phenyl, unsubstituted or substituted with one or more suitable substituents.
Examples of preferred compounds of formula I include: 
The present invention is also directed to a method of inhibiting picornaviral 3C protease activity, comprising contacting the protease with an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, pharmaceutically active metabolite, or solvate thereof. For example, picornaviral 3C protease activity may be inhibited in mammalian tissue by administering a compound of formula I or a pharmaceutically acceptable salt, prodrug, pharmaceutically active metabolite, or solvate thereof. More preferably, the present method is directed at inhibiting rhinoviral protease activity.
A xe2x80x9cprodrugxe2x80x9d is intended to mean a compound that is converted under physiological conditions or by solvolysis or metabolically to a specified compound that is pharmaceutically active. A prodrug may be a derivative of one of the compounds of this invention that contains a moiety, such as for example xe2x80x94CO2R, xe2x80x94PO(OR)2 or xe2x80x94Cxe2x95x90NR, that may be cleaved under physiological conditions or by solvolysis. Any suitable R substituent may be used that provides a pharmaceutically acceptable solvolysis or cleavage product. A prodrug containing such a moiety may be prepared according to conventional procedures by treatment of a compound of this invention containing, for example, an amido, carboxylic acid, or hydroxyl moiety with a suitable reagent. A xe2x80x9cpharmaceutically active metabolitexe2x80x9d is intended to mean a pharmacologically active compound produced through metabolism in the body of a specified compound. Prodrugs and active metabolites of compounds of this invention of the above-described Formulas may be determined using techniques known in the art, for example, through metabolic studies. See, e.g., xe2x80x9cDesign of Prodrugs,xe2x80x9d (Bundgaard, ed.), 1985, Elsevier Publishers B. V., Amsterdam, The Netherlands. A xe2x80x9cpharmaceutically acceptable saltxe2x80x9d is intended to mean a salt that retains the biological effectiveness of the free acids and bases of a specified compound and that is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, xcex3-hydroxybutyrates, glycollates, tartrates, methane-sulfonates (mesylates), propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates. A xe2x80x9csolvatexe2x80x9d is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound. Examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine. In the case of compounds, salts, or solvates that are solids, it is understood by those skilled in the art that the inventive compounds, salts, and solvates may exist in different crystal forms, all of which are intended to be within the scope of the present invention and specified formulas.
The activity of the inventive compounds as inhibitors of picornaviral 3C protease activity may be measured by any of the suitable methods known to those skilled in the art, including in vivo and in vitro assays. An example of a suitable assay for activity measurements is the antiviral H1-HeLa cell culture assay described herein.
Administration of the compounds of the formula I and their pharmaceutically acceptable prodrugs, salts, active metabolites, and solvates may be performed according to any of the accepted modes of administration available to those skilled in the art. Illustrative examples of suitable modes of administration include oral, nasal, parenteral, topical, transdermal, and rectal. Oral and intranasal deliveries are especially preferred.
An inventive compound of formula I or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof may be administered as a pharmaceutical composition in any pharmaceutical form recognizable to the skilled artisan as being suitable. Suitable pharmaceutical forms include solid, semisolid, liquid, or lyophilized formulations, such as tablets, powders, capsules, suppositories, suspensions, liposomes, and aerosols. Pharmaceutical compositions of the invention may also include suitable excipients, diluents, vehicles, and carriers, as well as other pharmaceutically active agents, depending upon the intended use. In preferred embodiments, the inventive pharmaceutical compositions are delivered intranasally in the form of suspensions.
The compounds (active ingredients) may be formulated into solid oral dosage forms which may contain, but are not limited to, the following active ingredients: diluents (i.e., lactose, corn starch, microcrystalline cellulose), binders (i.e., povidone, hydroxypropyl methylcellulose), disintegrants, (i.e., crospovidone, croscarmellose sodium), lubricants (i.e., magnesium stearate, stearic acid), colorants (FDandC lakes or dyes). Alternatively, the compounds may be formulated into other oral dosage forms including liquids, suspensions, emulsions, or soft gelatin capsules, with each dosage form having a unique set of ingredients.
Acceptable methods of preparing suitable pharmaceutical forms of the pharmaceutical compositions are known or may be routinely determined by those skilled in the art. For example, pharmaceutical preparations may be prepared following conventional techniques of the pharmaceutical chemist involving steps such as mixing, granulating, and compressing when necessary for tablet forms, or mixing, filling, and dissolving the ingredients as appropriate, to give the desired products for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraaural, and/or rectal administration.
Solid or liquid pharmaceutically acceptable carriers, diluents, vehicles, or excipients may be employed in the pharmaceutical compositions. Illustrative solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, pectin, acacia, magnesium stearate, and stearic acid. Illustrative liquid carriers include syrup, peanut oil, olive oil, saline solution, and water. The carrier or diluent may include a suitable prolonged-release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. When a liquid carrier is used, the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g., solution), or a nonaqueous or aqueous liquid suspension.
A dose of the pharmaceutical composition contains at least a therapeutically effective amount of the active compound (i.e., a compound of formula I or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof), and preferably is made up of one or more pharmaceutical dosage units. The selected dose may be administered to a mammal, for example, a human patient, in need of treatment mediated by inhibition of picornaviral 3C protease activity, by any known or suitable method of administering the dose, including topically, for example, as an ointment or cream; orally; rectally, for example, as a suppository; parenterally by injection; or continuously by intravaginal, intranasal, intrabronchial, intraaural, or intraocular infusion. A xe2x80x9ctherapeutically effective amountxe2x80x9d is intended to mean the amount of an inventive compound that, when administered to a mammal in need thereof, is sufficient to effect treatment for disease conditions alleviated by the inhibition of the activity of one or more picornaviral 3C proteases, such as human rhinoviruses, human poliovirus, human coxsackieviruses, encephalomyocarditis viruses, menigovirus, and hepatitis A virus. The amount of a given compound of the invention that will be therapeutically effective will vary depending upon factors such as the particular compound, the disease condition and the severity thereof, the identity of the mammal in need thereof, which amount may be routinely determined by artisans.
Syntheses
Examples of various preferred compounds of formula I are set forth below. The structures of the compounds of the following examples were confirmed by one or more of the following: proton magnetic resonance spectroscopy, infrared spectroscopy, elemental microanalysis, mass spectrometry, thin layer chromatography, melting-point determination, and boiling-point determination.
Proton magnetic resonance (1H NMR) spectra were determined using a Bruker or a Varian UNITYplus 300 spectrometer operating at a field strength of 300 megahertz (MHz). Chemical shifts are reported in parts per million (ppm, xcex4) downfield from an internal tetramethylsilane standard. Alternatively, 1H NMR spectra were referenced to residual protic solvent signals as follows: CHCl3=7.26 ppm; DMSO=2.49 ppm; C6HD5=7.15 ppm. Peak multiplicities are designated as follows: s=singlet; d=doublet; dd=doublet of doublets; t=triplet; q=quartet; br=broad resonance; and m=multiplet. Coupling constants are given in Hertz. Infrared absorption (IR) spectra were obtained using a Perkin-Elmer 1600 series FTIR spectrometer. Elemental microanalyses were performed by Atlantic Microlab Inc. (Norcross, Ga.); results of the microanalyses are stated within xc2x10.4% of the theoretical values. Flash column chromatography was performed using Silica gel 60 (Merck Art 9385). Analytical thin layer chromatography (TLC) was performed using precoated sheets of Silica 60 F254 (Merck Art 5719). Melting points (abbreviated as mp) were determined on a Mel-Temp apparatus and are uncorrected. All reactions were performed in septum-sealed flasks under a slight positive pressure of argon, unless otherwise noted. All commercial reagents were used as received from their respective suppliers.
In addition, for convenience a number of abbreviations are used. Solvents are denoted CH3OH (methanol); DME (ethylene glycol dimethyl ether); DMF (N,N-dimethylformamide); DMSO (dimethylsulfoxide); Et2O (diethyl ether); EtOAc (ethyl acetate); EtOH (ethanol); and MTBE (tert-butyl methyl ether). Certain substituents are referred to as Ac (acetyl); Me (methyl); Ph (phenyl); and Tr (triphenylmethyl). Protecting groups are abbreviated Cbz (benzyloxycarbonyl) and Boc (tert-butoxycarbonyl).
Various reagents used were denoted BINAP (2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl); DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); DCC (dicyclohexylcarbodiimide); DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone); DIBAH (diisobutyl aluminum hydride); DIEA (N,N-diisopropylethylamine); DMAP (4-dimethylaminopyridine); EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride); HATU (O-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate); HOBt (1-hydroxybenzotriazole hydrate); IBX (1,1-dihydro-1,2-benziodoxol-3(1H)-one); LiHMDS (lithium bis(trimethylsilyl)amide); Pd-C (10% palladium on carbon); PyBOP (benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate); TBAF (tert-butyl ammonium fluoride); TBSCl (tert-butyl dimethylsilyl chloride); and TFA (trifluoroacetic acid).